John, hope this helps when you see the surgeon, if not email me on the usual address - mtce2006@yahoo.com
Over 250 years have elapsed since induratio penis plastica was first described by Francois Gigot de la Peyronie, surgeon to Louis XV. This benign condition of the penis has been the subject of voluminous literature but little in the way of reliable medical therapies. Although the symptoms and signs are uncomplicated, a balanced and cautious approach to the management of these patients is required to achieve optimum long term satisfaction.
Peyronie's disease is estimated to affect between 1 and 3% of the male population with a peak incidence occurring in the fifth decade. A questionnaire-based study of over 4000 respondents found that 3.2% of the respondents between the ages of 30 and 80 years reported palpable plaques in the penis. The classic presenting symptoms are curvature of the erect penis, penile pain, erectile dysfunction and the presence of a palpable plaque arising from the tunica albuginea. The plaques may progress to become nodular with very severe cases showing signs of calcification and ossification. Complete spontaneous resolution can occur in 13-40% of patients. The disease has also been reported to occur in association with other conditions (Dupuytren's contracture, Ledeshore's disease, Tympanosclerosis, Paget's disease, and Diabetes) indicating a likely genetic predisposition or a possible underlying autoimmune basis for disease initiation and progression. Globally, the incidence of this condition appears to be increasing. This may be indicative of the wider availability and use of oral pharmacotherapies in impotent men, which allows identification of those patients who would otherwise have been unaware that they had a penile curvature. This also reflects the greater awareness of male sexual dysfunction within our society due to broad media coverage and the acceptance that conditions such as Peyronie's disease can be openly discussed and brought to the attention of primary care practitioners without embarrassment.
The normal tunica albuginea of the penis is composed of a lattice of collagen and elastic fibres which are arranged in two layers: an outer longitudinal laver responsible for elongation of the penis during erection and an inner circular layer responsible for increasing the width. Emissary veins and arterial branches traverse the layers of the tunica and allow communication between the erectile tissue and the dorsal vasculature of the penis. During the early phases of the disease, cellular infiltrates consisting of T lymphocytes, macrophages and plasma cells surround the small vessels in the subtunical layer. This inflammatory infiltrate is later followed by focal areas of fibrosis that eventually develop into mature plaques.
Histological examination of excised plaques shows that fibrin deposition occurs within the plaques together with dense collagenous connective tissue and calcification. Areas of fibrosis may then extend into the erectile tissue as well as transgressing the tunical layer.
There are several theories which have been proposed to explain the disease process occurring in Peyronie's disease. The most widely accepted theory is that the disease process is initiated by tunical mechanical stress and microvascular trauma to the erect penis which results in aberrant wound healing and subsequent scar tissue formation. Alternative theories suggest that plaque formation is a manifestation of an autoimmune disease initiated by an infectious agent. A genetic predisposition may also have a role since Peyronie's disease is associated with other fibrotic conditions such as Dupuytren's contracture (10-20% incidence in Peyronie's disease) and Ledeshore's disease as well as human lymphocyte antigen (FILA)-B7 antigens.
Peyronie's disease presents in two distinct phases, an inflammatory phase lasting approximately 3-12 months where patients develop progressive penile curvature and penile pain followed by a chronic phase characterized by stable plaque formation and a variable degree of erectile dysfunction.
Mechanical stress and microvascular trauma
The imbalance between profibrotic and antifibrotic factors plays a key role in the ultimate development of a tunical plaque. As mentioned already, the initiating factor appears to be microvascular trauma occurring during sexual intercourse. This leads to subtunical bleeding and delamination of the tunica albuginea with subsequent fluid and fibrinogen leakage into the subtunical layers. Extravascular leakage of blood results in the release of platelet-derived growth factors such as MGF-A and MGF-B and also transforming growth factor (TGF)-B1.
Immunohistochemical studies have shown strong expression of MGF-A and PDGF-B in fibroblast-like cells in the tunica albuginea obtained from patients with Peyronie's disease. Thrombogenesis and deposition of fibrin leads to the initiation of the wound healing response with macrophage, neutrophil and mast cell recruitment. Neutrophils are the predominant inflammatory cell type in the first 24 hours and macrophage recruitment occurs at 48 hours. The release of cytokines and vasoactive factors initiates the fibrogenesis. The subsequent migration and proliferation of fibroblasts in response to growth factors released by platelets and macrophages is followed by fibroblast differentiation into myofibroblasts. In normal wound healing the paracrine effects of growth factors assist in wound closure following which the myofibroblasts undergo apoptosis. It is postulated that in certain conditions, e.g. Dupuytren's disease, these myofibroblasts persist resulting in abnormal fibrosis. It is plausible that a similar mechanism occurs in plaque development during Peyronie's disease.
Plaque development and TGF-ß1
TGF-ß1 appears to increase the synthesis of collagen, proteoglycans and fibronectin in addition to the tissue inhibitors of collagenase, the overall result being that fibrogenesis is potentiated. TGF-ß1 is synthesized by various cell types including platelets, fibroblasts and macrophages as an inactive, latent peptide. Once activated, TGF-ß1 binds to specific cell surface receptors and not only activates a signal cascade leading to the synthesis of connective tissue but also simultaneously inhibits collagenases. Evidence for the role of TGF-ß1 in the pathogenesis of Peyronie's disease has been gathered from both human and animal studies. Increased expression of TGF-ß1, TGF-ß2 and TGF-ß3 has been found in patients with Peyronie's disease when compared with non-Peyronie's patients using plaque and tunica albuginea biopsies. Further evidence for the role of TGF-ß1 appears from a rat model of Peyronie's disease utilizing subtunical injections of the synthetic heptapeptide cytomodulin which stimulates TGF-ß1 expression. After 6 weeks of cytomodulin injection, tunical thickening and plaque formation occurred. In addition to this TGF-ß1 mRNA expression was found to have increased.
TGF-ß1 also transcriptionally represses inducible nitric oxide synthase (iNOS) production therefore overall nitric oxide (NO) production is reduced. The antifibrotic effects of NO will be discussed later.
Reactive oxygen species
Reactive oxygen species (ROS) are highly reactive oxidizing agents and include superoxide anion (O2), hydrogen peroxide (H202), and the nitrogen-derived free radicals NO and peroxynitrite anion (ONOO-). The localized inflammatory reaction following penile trauma may result in excessive ROS generation. The presence of ROS can activate a range of cellular mediators implicated in the inflammatory phase of the disease process. Cell membrane lipid peroxidation due to the presence of free radicals results in an increase in vascular permeability. This is followed by leakage of fibrogenic factors and subsequent activation of fibroblasts, neutrophils and macrophages. This forms the basis for the use of free radical scavengers and antioxidants as a therapeutic option in Peyronie's disease. NO has an antioxidant effect on ROS leading to the production of peroxynitrite. Additionally, elimination of ROS by antioxidant enzymes such as superoxide dismutase, catalase and xanthine oxidase can also occur. Therefore it appears that an overall imbalance between ROS and NO can result in fibrogenesis. The complex antifibrotic effects of NO are not exclusively through reducing the levels of ROS but may also involve modulating the fibrogenic activity of endothelin and angiotensin. It may also stimulate the activity and expression of metalloproteinases.
Clinical features - how the penis is affectedHistory
The most common presenting symptom of Peyronie's disease is penile deformity followed by pain. Penile deformity can occur in up to 90% of men although the incidence of pain varies between 20 and 70%. Studies reviewing sexual dysfunction in untreated patients with Peyronie's disease found that 2-11% of patients complain of problematic sexual intercourse due to severe penile angulation making coitus impossible. In 1-40% of men, sexual intercourse was unsatisfactory due to pain and 3% of patients complained of distal penile flaccidity.
There are two distinct phases in the natural history of Peyronie's disease. The initial inflammatory phase, characterized by progressive penile curvature and pain, can last for 12 months followed by a stable painless phase. It is important to avoid surgical intervention during the inflammatory phase. The evaluation of a patient presenting with Peyronie's disease should include a thorough medical and sexual history. This will help to differentiate between the early and late phases of the disease and whether any medical or surgical intervention is indicated.
Examination
Classically, a Peyronie's plaque is found in the dorsal midline of the penile shaft. Lateral and ventral plaques are less common, however, if they are present there is a significant deviation of the natural angle of coitus thus making sexual intercourse particularly problematic. More complex plaques can be circumferential resulting in an hourglass deformity of the penis with distal penile flaccidity. Gentle stretching of the penis helps in identifying the site and size of the plaques which should be recorded diagrammatically to assist in the monitoring of plaque progression. The stretched penile length is measured from the urethral meatus to the level of the abdominal skin. Penile shortening usually occurs even before surgical intervention. In order to monitor disease progression, the angle of deformity is documented using either an intracavernosal injection of a vasoactive agent or digital photography. The use of vasoactive intracavernosal injections is also useful in patients who have concomitant erectile dysfunction.
Erectile dysfunction associated with Peyronie's disease may be due to a combination of factors.
Psychogenic: the presence of an obvious penile deformity can precipitate anxiety-related erectile dysfunction. This feature is more common in early relationships as opposed to longstanding relationships.
Hourglass deformity: circumferential plaques can prevent adequate tumescence of the distal segment of the penis. This lack of rigidity can result in problematic penetration. [This is effectively erectile dysfunction caused by deformity, which may be the kind of erectiel dysfunction from which you are suffering.]
Vasculogenic: erectile dysfunction may be due to concomitant vascular disease that occurs in 30% of patients with Peyronie's disease or site specific veno-occlusive dysfunction. An emissary vein may pass through a Peyronie's plaque into the dorsal vein of the penis and cannot be compressed between the tunical layers. Patients may then present with a flaccid distal portion of the penis or a soft glans penis, the proximal segment being normal. There is controversy as to the mechanism of this, be it arterial, venous or fibrotic in nature but certainly a significant symptom of advanced organic disease. Extensive investigations are not always required in the early stages of the disease. The diagnosis can be made with a thorough history and examination. However, in patients who are being considered for surgery, imaging techniques can assist in delineating the plaques and accurately assessing the preoperative erectile function.
Colour Doppler ultrasound and magnetic resonance imaging
Colour Doppler studies performed before and after the injection of vasoactive agents allow more detailed assessment of the areas of involvement and plaque dimensions. The arterial and venous flow can be assessed, particularly if preoperative erectile dysfunction is also present or the true extent of the dysfunction is still unclear. Severe vasculogenic erectile dysfunction which has not been helped using phosphodiesterase inhibitors indicates that surgical correction of the penile deformity will not necessarily improve potency postoperatively. Therefore a penile implant is an appropriate alternative. Contrast-enhanced magnetic resonance imaging (MRI) is reserved for patients with complex and extensive cavernosal fibrosis. The fibrosis can often be seen extending deep into the erectile tissue of the corpus cavernosum resulting in significant hourglass deformities.
Oral treatment options
Since oxidative stress and activation of collagen synthesis have been widely implicated in disease progression, pharmacotherapies have specifically targeted these two pathways in the form of antioxidants and collagen synthesis inhibitors. Generally, pharmacotherapies are found to be most efficacious in the inflammatory phase of the disease process.
Vitamin E (alpha-tocopherol)
Vitamin E is an antioxidant which is used to prevent fibrosis with no reported side effects. It interacts with ROS such as OH. and reduces the molecule to an inert state. Although early studies reported a significant reduction in the penile curvature and reduction in plaque size, larger cohorts have shown between 35 and 99% of patients report a decrease in pain with only 10-33% reporting an improvement in penile angulation.
With debatable overall improvement in the degree of deformity, vitamin E still has a limited role in the management of early Peyronie's disease.
Potaba (potassium para-aminobenzoate)
Oral Potaba increases monoamine oxidase, decreases serotonin, increases oxygen utilization and therefore reduces overall free radical generation. Potaba inhibits abnormal fibroblast proliferation, acid mucopolysaccharide and glycosaminoglycan secretion and thus has a wide variety of uses in chronic inflammatory disorders including pulmonary fibrosis and scleroderma.
However, the use of Potaba is fraught with limitations including the high dosage regime (12 g per day), high cost and gastrointestinal side effects. Evidence for the efficacy of Potaba is also limited with studies being of small size and generally uncontrolled. A placebo controlled double-blind trial of 41 patients showed no statistically significant benefit at all.
Colchicine
An alkaloid derivative from the autumn crocus, Colchicum autumnale, colchicine binds to tubulin and interferes with microtubular structure and function. Colchicine is likely to have several other mechanisms of action which include inhibiting the release of inflammatory cytokines and inhibiting phospholipase A2 which also reduces eicosanoid production. In vitro studies have demonstrated that colchicine inhibits the proliferation of fibroblasts cultured from Peyronie's plaques. Colchicine -treated animals also demonstrate a reduction in collagen deposition in the tunica albuginea. Clinical trials using ultrasound techniques to measure plaque size and intracavernosal injections to measure penile angulation have shown that there is 70-95% improvement in pain and 30-55% improvement in the penile angulation. Overall efficacy is improved in patients who have had the disease for a short period and who have a penile curvature of less than 30 degrees.
Tamoxifen
This non-steroidal antioestrogen appears to modulate the inflammatory response by reducing TGF-ß1 secretion from fibroblasts. As previously stated TGF-ß1 not only stimulates the synthesis of connective tissue matrix, but also inhibits matrix degrading proteases. As with colchicine, tamoxifen treatment is most efficacious in patients with early disease but there are still conflicting data regarding the efficacy in Peyronie's disease. An early clinical trial reported an improvement in pain of 80% with improved angulation of 35% when tamoxifen was taken at a dose of 20 mg twice daily for at least 3 months. However, a randomized placebo controlled study found no significant improvement in pain or angulation.
Intralesional injection treatment
Both verapamil and interferon-alpha have been instilled directly into the Peyronie's plaque. Although there are limited data, there does appear to be a degree of symptomatic improvement in these patients.
Verapamil
It has become evident that exocytosis of extracellular matrix molecules including collagen and glycosaminoglycans is a calcium-mediated event. The use of calcium antagonists results in a morphological change of the fibroblasts resulting in an alteration in the secreted protein phenotype. Verapamil inhibits collagen synthesis and is effective in plaque softening and dissolving when injected intralesionally. Recent studies have shown that verapamil inhibits the expression of collagen and increases the activity of collagenase. Expression of cytokines including PDGF-BB, interleukin IL-6 and IL-8 which have an important role in the early phases of the wound healing response is also altered.
However, clinical data is limited due to the lack of controlled studies. The most recent studies utilizing verapamil have shown an improvement in pain severity and penile angulation regardless of the duration and severity of the angulation. Other studies have reported pain resolution in 97% of patients and penile curvature was reduced by 54% when injections were used every 2 weeks for 12 weeks. In a more recent series, with a follow-up of up to 6 years, 60% of men reported an objective decrease in the curvature with very few complications being reported. Long term follow-up did not show further disease progression in this group of patients.
Interferon-alpha-2b
Interferons (IFNs) are a group of low molecular weight proteins and glycoproteins. The potential usage of interferons developed from in vitro work using Peyronie's-derived human fibroblasts and the known effects of IFN-alpha2b in decreasing keloid scars. Evidence for the use of intralesional IFN-alpha2b is conflicting. However, studies which have found no significant effect from utilizing IFN-alpha2b appear to have injected in the tissue adjacent to the plaque as opposed to intralesionally. Support for the use of IFN-alpha2b has been reported in relatively small studies. Intralesional injection of IFN-alpha2b two to three times a week over a period of up to 6 months produced a significant improvement in the penile curvature.
Extralesional therapy
Extracorporeal shock wave therapy
Although extracorporeal shock wave therapy (ESWT) has a well established role in the management of renal calculi, in recent years a few studies have reported the safety, tolerability and efficacy of ESWT in the treatment of Peyronie's disease. In patients who have had unsuccessful oral therapy, ESWT has resulted in a significant reduction in the penile curvature. ESWT has also been reported to improve erectile function in patients with Peyronie's disease. In a recent study, 28 patients underwent three to nine ESWT sessions. A total of 71 % reported significantly improved erection and 49% were able to recommence sexual intercourse. However, until ESWT has been evaluated in larger sample populations, there still remains significant doubt as to whether this form of treatment will become routine.
Radiotherapy
Low-dose radiotherapy has been utilized in the treatment of Peyronie's disease. Patients irradiated with orthovoltage radiotherapy (200 and 250 kV photons) with a total dose of 9 Gy have reported less pain (65%), reduced curvature (40%) and an improvement in their sex life (50%). With a higher dose of radiotherapy 83% reported that pain had diminished or disappeared and 23% reported a decrease in penile curvature. It is recommended that radiotherapy be reserved as a treatment option in cases of continuing pain after other treatment modalities have been used. It may be particularly useful in the management of older patients with multiple co-morbidities.
Surgical management of Peyronie's disease
Despite the diversity of medical treatments currently utilized for the early management of Peyronie's disease, penile straightening operations are still required in symptomatic patients with residual deformity. The aim of surgically correcting the penile deformity associated with Peyronie's disease is to allow penetrative sexual intercourse with minimal complications and shortening of the penis. Currently, the surgical procedures choice are: 1) Nesbit procedure 2) plaque incision and grafting techniques 3) penile prosthesis. Patients with dorsal deformities less than 45 degrees may be able to manage without surgery. Younger patients, or those with ventral or lateral curvatures which make penetration more difficult, tend to have lesser degrees of curvature corrected.
Nesbit procedure
The Nesbit procedure was first described in 1965 to correct congenital penile curvature and an overall success rate of 82% has been quoted when the procedure is used to correct penile angulation due to Peyronie's disease. Patients should only be considered for a Nesbit procedure following a thorough evaluation of the disease history and progression. Once it is established that the disease has entered the stable phase, full informed consent should be obtained with particular emphasis placed on the inevitable risk of penile shortening following the procedure and the risk of erectile dysfunction.
The Nesbit procedure involves a routine circumcision followed by degloving of the penile skin. A saline artificial erection is induced and the plaque is located. Bucks fascia is then completely elevated to allow mobilization of the neurovascular bundle and the urethra. Ellipses of tunica are excised from the convex surface of the penis opposite the plaque with 1 mm of tunica excised for every 10 degrees of deformity. The defects are closed with poorly absorbable sutures (O-PDS) with the knots buried on the inside. Although the long term results of a Nesbit procedure are good, both short term (within 8 weeks) and long term failures can present with residual penile deformity. Where failures require revision surgery it is essential to ensure that the disease is stable and painless before considering a salvage operation. It is imperative that the preoperative erectile function is assessed using a combination of vasoactive agents and colour Doppler ultrasound as patients with preoperative erectile impairment have a reduced satisfaction rate of 74-77%.
A further technique now commonly used as an adjunct during surgery is known as corporal plication. This technique uses multiple non-absorbable plication sutures on the contralateral side of the plaque without the need to excise the tunica or incise the plaque. These plication sutures are most commonly used in association with a Nesbit or a Lue procedure to correct small angles of residual penile deformity. If used in isolation in Peyronie's disease, penile shortening is inevitable and the long term results are not comparable with a failure rate of up to 24%.
Tunical Grafting Techniques
Plaque excision and grafting is considered to be an obsolete operation.
By contrast, the Lue procedure involves incising the plaque followed by grafting of the defect using an autologous vein patch. Although vein patches from the dorsal penile vein have been used, the saphenous vein is now used more routinely. The plaque is incised in the shape of an H and the resulting rectangular defect is closed using a vein patch which has the endothelium directed adjacent to the erectile tissue. Recent studies have shown excellent or satisfactory outcome in 92% of patients. Penile shortening may still occur, but to a lesser extent than with a Nesbit procedure. The incidence of postoperative erectile dysfunction is 5-12%. Following the operation, patients are advised to abstain from sexual intercourse for a 6-week period. Thereafter, if the recovery is uncomplicated, they can commence sexual activity. A proportion of these patients will require the concomitant use of oral PDE-5 inhibitors.
Insertion of a penile prosthesis
The combination of severe erectile dysfunction and penile deformity due to Peyronie's disease can be managed by using a penile prosthesis. This is particularly useful in elderly patients with diabetes related erectile dysfunction [check that you do not have diabetes, since it runs in your family] in whom oral pharmacotherapies are unlikely to be successful. If mild to moderate penile curvature is present, the insertion of a penile prosthesis can restore penile length as well as correct the penile deformity with a high rate of success.
John, hope this helps when you see the surgeon, if not email me.